Periodic Reporting for period 1 - Need2immune (Personalized liposomal cancer vaccines within days by rapid formulation screening)
Periodo di rendicontazione: 2019-09-01 al 2021-08-31
Cancer immunotherapy is defined as the ability to mobilise the host’s own immune system to kill cancer, has recently taken a central role within mainstream oncology. This period has seen unprecedented clinical responses in patients coinciding with the development of novel classes of immunotherapeutic drugs. One of the challenges in the future will be to understand how best to administer these molecules since the current approach of systemic administration harbours the risk of causing serious toxicity and/or autoimmunity. Currently, cancer immunotherapies are injected into the bloodstream where there are many drawbacks. It could be more effective therefore to inject this kind of therapy locally and directly to target tumour cells with also for lower doses to be administered. The overall goal of this project was therefore to use microneedles to deliver LOCAL nanoparticle doses of combined immunotherapies, as the focus of a novel approach to developing new strategies for delivery of onco-immunotherapeutic agents.
In this project a hollow microneedle system was developed for LOCAL delivery of nanoparticles, by which immunomodulatory were injected into tumours. Furthermore, a wide range of lipid nanoparticles were synthesized in this project, which incorporated near-infrared fluorescent dyes and immune modulating agents. These nanoparticles were tested on cell cultures and animals for the induction of cancer-specific immune responses and tumour control. The results that were obtained in these studies proved that cationic nanoparticle formulations injected LOCAL resulted in superior immune responses and tumour regression. The overall conclusion of this project is that novel knowledge was developed to more rationally design procedures for optimal delivery and efficacy of cancer immunotherapy.
In this project a hollow microneedle system was developed for LOCAL delivery of nanoparticles, by which immunomodulatory were injected into tumours. Furthermore, a wide range of lipid nanoparticles were synthesized in this project, which incorporated near-infrared fluorescent dyes and immune modulating agents. These nanoparticles were tested on cell cultures and animals for the induction of cancer-specific immune responses and tumour control. The results that were obtained in these studies proved that cationic nanoparticle formulations injected LOCAL resulted in superior immune responses and tumour regression. The overall conclusion of this project is that novel knowledge was developed to more rationally design procedures for optimal delivery and efficacy of cancer immunotherapy.
In this project an extensive review of the scientific literature about nanoparticles and microneedles for the immunotherapy of cancer was made. From this extensive literature research two manuscripts were drafted and published in peer-reviewed open access scientific journals (see below). These review articles provide a wide scientific public novel insights, based on the most recent data from the scientific literature.
- Liposome-Based Drug Delivery Systems in Cancer Immunotherapy (Pharmaceutics 2020, 12(11):1054), were different liposomal systems specifically developed for immunomodulation in cancer are summarized and discussed (i.e. Vaccination, Tumor normalization, Rewiring of tumor signaling, and Combinational therapy).
- Cationic Nanoparticle-Based Cancer Vaccines (Pharmaceutics 2021, 13(5):596), where the relation between the cationic nature of nanoparticles and the efficacy of cancer immunotherapy are discussed as well as Multiple types of lipid- and polymer-based cationic nanoparticulate cancer vaccines with various antigen types (e.g. mRNA, DNA, peptides and proteins). Moreover, in this review the types of cationic nanoparticles used for T-cell induction, especially in the context of therapeutic cancer vaccination are discussed.
Furthermore, a new method and system was developed to fabricate novel dissolvable microneedle structures on a verry controlled manner via nanolitre-size droplets. Based on this work a manuscript was prepared, which was published in a peer reviewed journal (Int J Pharm 2021, 600:120473). The published system and methodology are currently being further exploited for their potential use for intradermal cancer immunotherapy.
In this project a novel hollow microneedle system was developed for LOCAL delivery of nanoparticles as well as lipid nanoparticles containing an immunomodulating drug (STING agonist). The lipid nanoparticles have shown to be very potent in cell assays and the hollow microneedle system enabled us to inject volumes below 1 µL accurately into a solid tumour. Follow up experiments are planned to investigate the efficacy of intratumorally injected lipid nanoparticles for tumor regression in animal studies.
Finally, in this project a wide range of lipid nanoparticles were synthesized, which were formulated with a near-infrared fluorescent dye and a peptide-based cancer vaccine. These nanoparticles were evaluated in cell cultures and animals for the induction of cancer-specific immune responses and tumour control. From these studies a selection of potent cancer vaccine candidates were obtained that induced high cancer-specific immune responses and showed effective tumour control (manuscript in preparation).
- Liposome-Based Drug Delivery Systems in Cancer Immunotherapy (Pharmaceutics 2020, 12(11):1054), were different liposomal systems specifically developed for immunomodulation in cancer are summarized and discussed (i.e. Vaccination, Tumor normalization, Rewiring of tumor signaling, and Combinational therapy).
- Cationic Nanoparticle-Based Cancer Vaccines (Pharmaceutics 2021, 13(5):596), where the relation between the cationic nature of nanoparticles and the efficacy of cancer immunotherapy are discussed as well as Multiple types of lipid- and polymer-based cationic nanoparticulate cancer vaccines with various antigen types (e.g. mRNA, DNA, peptides and proteins). Moreover, in this review the types of cationic nanoparticles used for T-cell induction, especially in the context of therapeutic cancer vaccination are discussed.
Furthermore, a new method and system was developed to fabricate novel dissolvable microneedle structures on a verry controlled manner via nanolitre-size droplets. Based on this work a manuscript was prepared, which was published in a peer reviewed journal (Int J Pharm 2021, 600:120473). The published system and methodology are currently being further exploited for their potential use for intradermal cancer immunotherapy.
In this project a novel hollow microneedle system was developed for LOCAL delivery of nanoparticles as well as lipid nanoparticles containing an immunomodulating drug (STING agonist). The lipid nanoparticles have shown to be very potent in cell assays and the hollow microneedle system enabled us to inject volumes below 1 µL accurately into a solid tumour. Follow up experiments are planned to investigate the efficacy of intratumorally injected lipid nanoparticles for tumor regression in animal studies.
Finally, in this project a wide range of lipid nanoparticles were synthesized, which were formulated with a near-infrared fluorescent dye and a peptide-based cancer vaccine. These nanoparticles were evaluated in cell cultures and animals for the induction of cancer-specific immune responses and tumour control. From these studies a selection of potent cancer vaccine candidates were obtained that induced high cancer-specific immune responses and showed effective tumour control (manuscript in preparation).
Until recently cancer immunotherapy has focused on tumour-associated and overexpressed self-antigens, for which it is very difficult to break the immune tolerance through vaccination. However, where combined with checkpoint modulating drugs, this could maximise the overall immune response of the host. In this project multiple immune reagents were combined in nanoparticle carriers, e.g. STING agonists with cationic adjuvanting lipids, which have shown to be very potent in cellular assays. Besides, an optimized microneedle delivery system with a dedicated microfluidics pump connected to the microneedle was developed to locally deliver immunotherapeutic drugs into tumours, which potentially offers improved cancer treatments with less side effects through microneedle-targeted drug delivery (e.g. when used in combination with chemotherapeutic drugs). The developed nanoparticle formulations in combination with the novel microneedle system are to be further evaluated for their ability to induce immune responses and tumour regressions in preclinical studies. Furthermore, a large range of lipid nanoparticles with varying physicochemical properties (negative, neutral, positive surface charge) were formulated with cancer-specific peptides and near-infrared-fluorescent dyes and were evaluated for their biodistribution, revealing which formulation parameters and pharmacokinetic profiles are associated with improved immune responses and tumour control. Concluding, in this project new scientific insights into critical immunotherapy lipid nanoparticulate formulation parameters were obtained as well as a novel injection method. Based on the obtained results, novel cancer vaccines can be more rationally designed for optimal delivery and efficacy (e.g. choice of lipids, surface charge of nanoparticle, type of cancer antigen), and thereby potentially improving future cancer treatments.